Reduced activation of protein kinase B, Rac, and F-actin polymerization contributes to an impairment of stromal cell–derived factor-1–induced migration of CD34+ cells from patients with myelodysplasia

Abstract

Patients with myelodysplasia (MDS) show a differentiation defect in the multipotent stem-cell compartment. An important factor in stem-cell differentiation is their proper localization within the bone marrow microenvironment, which is regulated by stromal cell-derived factor (SDF-1). We now show that SDF-1-induced migration of CD34 ؉ progenitor cells from MDS patients is severely impaired. In addition, these cells show a reduced capacity to polymerize F-actin in response to SDF-1. We demonstrate a major role for

Distinctive contact between CD34+ hematopoietic progenitors and CXCL12+ CD271+ mesenchymal stromal cells in benign and myelodysplastic bone marrow

“…7 Strong CXCL12 expression by CD271 þ ALP þ MSCs could be a source of abnormal survival/proliferation signaling for adjacent neoplastic CD34 þ HSPCs. CXCL12 is also involved in hematopoietic stem cell homing, 27 and isolated CD34 þ HSPCs from MDS patients are impaired in their ability to migrate toward CXCL12, 51 a finding that is associated with increased susceptibility to apoptosis in vitro. 28 Increased CXCL12 expression by MSCs could be part of a defective feedback loop between neoplastic CD34 þ HSPCs and altered MSCs in MDS.…”

Impact of substrate elasticity on human hematopoietic stem and progenitor cell adhesion and motility

“…In inhibition experiments, we could identify PI3K as one player in this process. PI3K was reported to be involved in the signaling cascade downstream of integrins (Giancotti and Ruoslahti, 1999;Melikova et al, 2004), the inside-out activation of integrins (Chrétien et al, 2010), the regulation of growth factor-dependent migration of cells (Fuhler et al, 2008;Zhang et al, 2001) and the mechanosensitive pathways induced by strain in endothelial, epithelial and muscle cells (Chrétien et al, 2010;Gayer et al, 2009;Pardo et al, 2008). All these processes might play a role in the transduction of a mechanical into a biochemical signal and the cell response with altered migration and adhesion.…”

“…4D). In order to delineate the signaling cues for this mechanosensing process, we targeted phosphatidylinositol-3-kinase (PI3K), which is involved in the regulation of cell adhesion, migration and mechanotransduction processes (Chrétien et al, 2010;Fuhler et al, 2008;Gayer et al, 2009;Giancotti and Ruoslahti, 1999;Melikova et al, 2004;Pardo et al, 2008;Zhang et al, 2001). Inhibition of PI3K with LY294002 impaired cell adhesion on both soft and hard gels.…”

TLR2 controls random motility, while TLR7 regulates chemotaxis of microglial cells via distinct pathways

“…Many studies have reported a cross-talk between Rho-GTPases and PI3K (Fuhler et al, 2008;Li et al, 2005;Servant et al, 2000). Rac is a member of the Rho family small GTP-binding proteins, which regulate the assembly of actin cytoskeletal structures associated with cell migration (Small et al, 1999), and is known to be a downstream signal of PI3K (Hall, 1998;Li et al, 2000a).…”